The underlying hypothesis of this study is that the complexity of cancer dictates that compared to single modalities, combination therapies that are mechanistically independent and which are directed at nonoverlapping molecular targets will additively or synergistically enhance treatment outcome. Toward achieving this goal, the current Program Project Grant (PPG) application builds on recent advances in the understanding of cancer biology, in mechanisms of current and emerging therapies as well as the enormous progress made in imaging technologies, to propose new photodynamic therapy (PDT)-based combination treatments for pancreato-biliary (PCBC) and non-melanoma skin cancers (NMSC) in an approach we term Combination Photodynamic Biologic Therapy (CPBT). PDT is a photochemistry-based modality that is approved for the treatment of a number of cancer and non-cancer pathologies. Strategically, these treatments response-enhancing CPBTs will be achieved in two ways: (i) by preconditioning tumors with agents which initiate molecular events that augment PDT, and (ii) by administering a second treatment specifically tailored to a particular molecular response elicited by the PDT. Optical imaging techniques will be invaluable for the online monitoring of light and photosensitizer dosimetry, treatment planning and molecular response. Project 1 will investigate molecular pathways affected by compounds that enhance ALA-PDT and can be exploited by a combination regimen to increase treatment response in skin carcinomas in models and in humans. Project 2 proposes to improve the survival and quality of life of patients with pancreatic or biliary tract carcinoma using PDT in clinical studies. Project 3 will build upon results from the previous funding cycle that PDT instigates molecular responses that can be targeted for much improved treatment outcomes. Preclinical models of pancreatic cancer (PanCa) will be used. Project 4 takes advantage of the advances in optical imaging to develop quantitative tools to monitor molecular features of tumors and their response to treatment, and to integrate them for the development of molecular-based combination therapies for standard clinical procedures. The proposed program will feature three cores that will provide support in three areas: Core A, through administration, scientific integration, education and career development, intellectual property development, and administration;Core B, through biological models, molecular pathology, and biostatistics;and Core C, through in vivo imaging, dosimetry, and the transfer of developed technologies to industry. It is anticipated that such rational, mechanism-based treatments will significantly benefit patient survival, quality of life and/or disease palliation and, combined with real-time imaging to monitor tumor progression and treatment response, provide patient-specific treatments that can be realistically envisioned. Potential benefits to public health: this program impacts on the treatment of three cancers: two of these PanCa and BTC which have few treatment options and are usually fatal. NMSC on the other hand has many options but the high incidence puts a heavy burden on society in terms of cost and suffering.